More specifically, this invention relates to certain cyclical hydroxylamines, to the synthesis thereof, and to compositions containing said compounds, such as pharmaceutical compositions adapted to the therapeutical use in the treatment of all those pathologies concerned with production, or an excess production, of oxygen-centered free radicals; the invention further relates to cosmetic compositions having anti-free radical activities, to the use of said cyclical hydroxylamines as additives to avoid rancidity of foodstuffs and deterioration of cosmetic products, and as a diagnostic means (marker) to reveal the status (of oxidative and/or inductive stress) at high carcinogenic risk and held responsible of other pathologies.
A number of normal and/or pathological processes are known in the course of which the formation of reactive radical species takes place. As a result of the general position of oxygen in aerobic organisms and also in human beings, as well as its high availability in accepting single electrons, the oxygen-centered free radicals very often are the protagonists of cellular reactions in physiopathology.
A plurality of conditions are also known to be capable of increasing the radical production within cells, such as a change in oxygen tension (in hyschemia, riperfusion, shock, transplants), lack of A, E vitamins, aging, administration of drugs of certain classes (halogen-alcanes, chemotherapy drugs, carcinogenic drugs, ethanol, paracetamol, etc.). There are also a plurality of conditions which increase the oxygen production in extra-cellular spaces, such as conditions arising from acute inflammatory states (infections, burns), chronic inflammatory states (rheumatoid arthritis, ulcerative colites, vasculites); immune disorders, immunocomplex pathologies, etc.
Moreover, antioxidant enzymes are also known for use as pharmacological agents and particularly it is known to use superoxide dismutase (SOD) in order to limit the excess production of said free radicals. This enzyme, of endogenous type, is capable of transforming the superoxide anion into oxygen and hydrogen peroxide, which will be later eliminated by catalase and peroxidase. This solution however has got quite a few problems arising from the poor stability of said enzyme the half life of which, once injected intravenously, ranges from about 6-8 minutes for the most commonly used form (Cu, Zn-SOD) to a few hours (Mn, PEG-SOD). Importantly, said enzymes, both native or modified, are obtained by cloning human genes and have activities modified by site-specific mutagenesis, which however involves high production costs.
A further disadvantage relevant to the use of said enzyme is the impossibility of achieving suitable concentrations of enzyme in the body areas where protection is required. To eliminate the above drawback, it is necessary to administer said enzyme in high and discontinuous dosages. However, since administration is intravenous, it is easy to understand that this methodology is not convenient.
Further, SOD, because of its large molecular dimensions, will not enter the intracellular environment, unless phagocytized by endothelial cells.
Although in order to obviate said problem, an attempt has been made to encapsulate the enzyme in specific vesicles having lipidic nature (the so-called `liposomes`) so as to make the passage easier through the double lipoproteinic layer of biological membranes, further problems have arisen related to the bio-technological process of realization and also to the difficulty of said liposomes to reach certain body areas through thin capillaries, in which the high blood flow rate do not allow a proper absorption of said liposomes into the specific tissue.
It is also known to coat liposomes with specific antibodies which will recognize the tissue where protection is required. This however introduces new limitations due to the high cost involved in preparing said antibodies.
It is also known to employ metal chelates, such as Mn; but besides dissociating very easily, said chelates have the further disadvantage of catalyzing undesirable redox processes in cells and also exhibit high affinity to proteins and amino acids.
A further disadvantage in the use of metal chelates is that said chelates may lose their activity upon binding to plural cellular components.
From scientific literature there is known oxane (2-ethyl-2,5,5-trimethyl-3-oxazolidonoxyl) which is currently the molecule with the best characteristics for acting as a `capturing agent` for superoxide.
Said oxanic derivative however has the drawback of being poorly lipophilic, which does not allow it, when administered, to readily pass through the double lipoproteinic layer of the biological membranes. In addition said derivative exhibits high synthesis costs.